Gene x environment interactions on brain and behaviour in the Cacna1c genetic rat model: Calcium signalling, microRNAs, and immune activation

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Affective disorders (AD), i.e. major depressive disorder (MDD) and bipolar disorder (BD), are phenotypes to which genetic and environmental risk factors contribute. The underlying neurobiological mechanisms by which such factors interact and how they exert their influence on brain structure and function are yet poorly understood. WP2, animal backbone of the FOR2107, addresses these questions by applying a gene x environment (GxE) approach in the Cacna1c genetic rat model. In the first funding period, we obtained substantial evidence for multiple behavioural alterations in Cacna1c+/- rats, including elevated anxiety-related behaviour, deficits in pre-pulse inhibition of acoustic startle under apomorphine challenge, reversal learning impairments in a spatial navigation task, and social behaviour and acoustic communication deficits. Of particular relevance for BD, the effectiveness of lithium in inhibiting mania-like phenotypes evoked by amphetamine was almost blunted in Cacna1c+/- rats. Environmental modulation of behavioural phenotypes was paralleled by GxE interactions at the level of neurobiological measures, immune activation, and epigenetic modifications. For instance, a widespread reduction in mature microRNA (miRNA) levels was detected in the hippocampus of Cacna1c+/+ rats in response to post-weaning social isolation (SI), as a model of maltreatment. Intriguingly, this effect was largely blunted in Cacna1c+/- rats. Specifically, the vast majority of miRNAs (>80%) was affected by the GxE interaction, indicating that most hippocampal miRNAs are subject to regulation by a combination of genetic and environmental factors (collab. WP3). Moreover, while post-weaning SI evoked immune reactivity characterized by elevated pro-inflammatory cytokines in Cacna1c+/+ rats, no such reactivity was seen in Cacna1c+/- rats, suggesting resilience (collab. WP4). In the second funding period, we will follow five lines of research in our established GxE Cacna1c rat model. We will (1) identify biopsychological mechanisms underlying social behaviour and acoustic communication deficits; (2) develop a novel behavioural assay for BD-like affective cycling; and (3) link alterations in calcium signalling components in prefrontal cortex and hippocampus to behavioural phenotypes with relevance to AD. Together with WP3, we will (4) further explore the impact of miRNA manipulations in prefrontal cortex and hippocampus by means of intracerebral injection of recombinant adeno-associated virus particles (rAAV), with the aim to rescue behavioural phenotypes relevant to AD after post-weaning SI through restoring miRNA biogenesis. Finally, with WP3 and WP4, we will (5) assess the impact of such miRNA biogenesis manipulations on immune signatures and, vice versa, the impact of immune challenges on AD-relevant phenotypes. Through this highly interconnected approach, the project promises novel insight regarding miRNA biogenesis and immune system in AD aetiology and treatment.